Latest trial of a virus engineered to kill cancer shows promise

Virus kills tumor cells, triggers an immune response to cancer.

For roughly 20 years, scientists have been working to engineer a virus that will attack cancer. The basic idea is sound, and every few years there have been some promising-looking results, with tumors shrinking dramatically in response to an infection. But the viruses never seem to go beyond small trials, and the companies making them always seem to focus on different things.

Over the weekend, Nature Medicine described some further promising results, this time with a somewhat different approach to ensuring that the virus leads to the death of cancer cells: if the virus doesn't kill the cells directly, it revs up the immune system to attack them. It's not clear this result will make it to a clinic, but it provides a good opportunity to review the general approach of treating cancer with viruses.

The basic idea is to leverage decades of work on some common viruses. This research has identified a variety of mutations keeping viruses from growing in normal cells. It means that if you inject the virus into a healthy individual, it won't be able to infect any of their cells.

But cancer cells are different, as they carry a series of mutations of their own. In some cases, these mutations compensate for the problems in the virus. To give one example, the p53 protein normally induces aberrant cells to undergo an orderly death called apoptosis. It also helps shut down the growth of viruses in a cell, which is why some viruses encode a protein that inhibits p53. Cancer cells tend to damage or eliminate their copies of p53 so that it doesn't cause them to undergo apoptosis.

So imagine a virus with its p53 inhibitor deleted. It can't grow in normal cells since they have p53 around, but it can grow in cancer cells, which have eliminated their p53. The net result should be a cancer-killing virus. (A great idea, but this is one of the viruses that got dropped after preliminary trials.)

In the new trial, the virus in question takes a similar approach. The virus, vaccinia (a relative of smallpox used for vaccines), carries a gene that is essential for it to make copies of itself. Researchers have engineered a version without that gene, ensuring it can't grow in normal cells (which have their equivalent of the gene shut down). Cancer cells need to reactivate the gene, meaning they present a hospitable environment for the mutant virus.

But the researchers added another trick by inserting a gene for a molecule that helps recruit immune cells (the awkwardly named granulocyte-macrophage colony-stimulating factor, or GM-CSF). The immune system plays an important role in controlling cancer, but it doesn't always generate a full-scale response to cancer. By adding GM-CSF, the virus should help bring immune cells to the site of the cancer and activate them, creating a more aggressive immune response to any cells that survive viral infection.

The study here was simply checking the tolerance for two different doses of the virus. In general, the virus was tolerated well. Most subjects reported a short bout of flu-like symptoms, but only one subject out of 30 had a more severe response.

However, the tumors did respond. Based on placebo-controlled trials, the average survival time of patients like the ones in the trial would have been expected to be about two to four months. Instead, the low-dose group had a survival time of nearly seven months; for the higher dose group, that number went up to over a year. Two of those treated were still alive after more than two years. Imaging of tumors showed lots of dead cells, and tests of the immune system indicate the virus had generated a robust response.

Will this virus finally make it out of clinical trials? Right now, the company that makes it is still engaged in phase 2 trials (like this one), which are designed to identify the treatment used for a large-scale effectiveness trial. There are still hurdles to overcome, but the promising results described here indicate the company behind it is very interested in seeing this through.

As a casual reader who isn't fully versed on this stuff I would like to ask:

Why can't this sort of thing be a preventative treatment? Basically inject people en masse with something like this and if someone unknowingly is in the first stages of a cancer, it eliminates it before it ever becomes a problem.

Is it just cost / time to manufacture? I'd think that would be surmountable.

While this is promising I just wish they could find a way to cure HIV and the like. Eventually they will, but I can't help but think I missed 'sexual revolution v.1.0' and will now be poised to miss 'sexual revolution v2.0' due to age. Youth is wasted on the young.

My guess might be a mutation problem. Widespread and indiscriminate use of antibiotics has led to some diseases developing resistant strains. Could a similar occurrence happen with whatever process creates cancer cells?

My guess might be a mutation problem. Widespread and indiscriminate use of antibiotics has led to some diseases developing resistant strains. Could a similar occurrence happen with whatever process creates cancer cells?

The only way this could be preventative is the virus could hang out in the body for years without any significant number of cancerous cells to host it (everyone has some cancerous cells at any given moment). That would make the virus a really hardy herpes-type thing that would be difficult to control if it mutated.

As a casual reader who isn't fully versed on this stuff I would like to ask:

Why can't this sort of thing be a preventative treatment? Basically inject people en masse with something like this and if someone unknowingly is in the first stages of a cancer, it eliminates it before it ever becomes a problem.

Is it just cost / time to manufacture? I'd think that would be surmountable.

Or is it something else?

Good question. So I've managed to sift through the materials and methods online. They injected the vector into the tumors:"we randomized patients centrally using permuted blocks to receive a dose of 10^9 or 10^8 PFU distributed among up to five intrahepatic tumors on days 1, 15 and 29. We administered JX-594 by imaging-guided IT injection using a multi-pronged Quadrafuse needle (Rex Medical Inc) to ensure even distribution of the virus throughout the tumor when possible (if this was not technically feasible, a straight needle was used)."Even if the virus could be given systemically, the recipient would generate a pretty strong anti-virus immune response so the curative vector wouldn't be around for long. Anti-cancer virus vectors tend to be the bigger, more complex ones, that can replicate, carry lots of genes, and whip up a nasty immune response. This is in contrast to the virus vectors used to treat single gene disorders, which tend to be small, gutted of any original viral genes, and more immunologically inert.

I have been wondering for a while if it is possible to create a bacterium that feeds on the shell proteins only found on viruses or certain viruses. Without these viruses the bacterium dies off after awhile and the body can clear them away. Seems reasonable to me.

It is too bad that it isn't possible to make a virus that attacks other viruses since they require cellular machinery to reproduce. That would be fascinating.

Another thought, I wonder if it is possible to make a virus that attaches to other viruses and destroys them (while attempting in vain to infect the other virus for reproductive purposes), but are unable to reproduce unless you provide it a supply of fake cells that have an outer membrane that resembles the virus' prey closely enough that it will be attacked and used for reproduction of the virus.

The thought here is you provide it the reproductive medium it needs while it attacks both the fake cells and the other virus molecules. When it's job is done you simply stop providing it with the fake cells and the virus can no longer propagate. Then the body's immune system can sweep away the remaining viruses. To be honest I don't really think this last idea has much, if any, possibility of being doable. But it is a thought.

I have been wondering for a while if it is possible to create a bacterium that feeds on the shell proteins only found on viruses or certain viruses. Without these viruses the bacterium dies off after awhile and the body can clear them away. Seems reasonable to me.

It is too bad that it isn't possible to make a virus that attacks other viruses since they require cellular machinery to reproduce. That would be fascinating.

Another thought, I wonder if it is possible to make a virus that attaches to other viruses and destroys them (while attempting in vain to infect the other virus for reproductive purposes), but are unable to reproduce unless you provide it a supply of fake cells that have an outer membrane that resembles the virus' prey closely enough that it will be attacked and used for reproduction of the virus.

The thought here is you provide it the reproductive medium it needs while it attacks both the fake cells and the other virus molecules. When it's job is done you simply stop providing it with the fake cells and the virus can no longer propagate. Then the body's immune system can sweep away the remaining viruses. To be honest I don't really think this last idea has much, if any, possibility of being doable. But it is a thought.

Given our current state of the art, you have to find such genes in nature first. AFAIK, we still aren't able to actually manufacture genes out of thin air, what people do with these virii is to find the genes they need and insert them into a known, previously emptied, virus.

Probably to make sure that 1/100 people doesn't drop dead for some reason.I doubt it's useless bureaucracy.

It's not useless bureaucracy. It's not just because of 1/100 (which, you'd be surprised how many "normal" meds kill people). It's because you WANT to make sure that things aren't going to go horribly awry.

People might knock it, the the reality is..... are we REALLY that spot-on with our biology skills that we can ensure something like this DOESN'T turn into something nasty? I mean, honestly, we have people that can't wrap their heads around evolution still. Mankind HAS screwed up in the past and with this kind of thing..... we're playing with stuff that we might not be able to control, or as the saying goes, "put the genie back into the bottle".

And yes, I have family members who are suffering from cancer as I type this. One of which being my dad. I also know he'd slap me upside the head if I were that selfish as to potentially risk EVERYONE at the sake of saving him. And I work in the medical field too, btw.

Probably to make sure that 1/100 people doesn't drop dead for some reason.I doubt it's useless bureaucracy.

It's not useless bureaucracy. It's not just because of 1/100 (which, you'd be surprised how many "normal" meds kill people). It's because you WANT to make sure that things aren't going to go horribly awry.

People might knock it, the the reality is..... are we REALLY that spot-on with our biology skills that we can ensure something like this DOESN'T turn into something nasty? I mean, honestly, we have people that can't wrap their heads around evolution still. Mankind HAS screwed up in the past and with this kind of thing..... we're playing with stuff that we might not be able to control, or as the saying goes, "put the genie back into the bottle".

And yes, I have family members who are suffering from cancer as I type this. One of which being my dad. I also know he'd slap me upside the head if I were that selfish as to potentially risk EVERYONE at the sake of saving him. And I work in the medical field too, btw.

They're already testing it on people, so if you're worried about it escaping the lab and decimating the planet, you're pretty much already screwed.

So volunteer yourself.Go. Hurry. Run and get an experimental treatment.

And if it makes your nuts drop off in 2 years, don't whine..

If your choices were dying in two months or living two years then having your bits fall off, which would you choose?

Normally I'd be wailing on the FDA since the downside is death and for terminally I'll patients that's almost irrelevant. But this has potential to spread and or cause mutations so there is some reason behind it.

I am not a medical professional, but I would imagine that the ultimate goal of this treatment would be to combine it with a chemotherapy drug injections at just the right time. You know, stab cancer in the back, and then piss on it's grave.

Dr. Tomoki Todo of the University of Tokyo (now with the university's Institute of Medical Science) has also seen favorable results with an engineered herpes virus used agains brain cancers (gliomas) in Phase I studies of tolerance. In one case, the results were nothing short of dramatic. However Phase I trials involve a very limited number of patients, and so technically one is not allowed to make claims regarding efficacy. More clinical trials are scheduled for this year.

If you can reach and inject the tumors with virus one-by-one. Why not inject or cover the tumors with Super-glue? I read about this treatment awhile back. The article claims that Super-glue cut-off the oxygen to the tumors and eventually the tumors died from lack of oxygen.

Probably to make sure that 1/100 people doesn't drop dead for some reason.I doubt it's useless bureaucracy.

You mean that's not established in Phase 1 and 2? Shouldn't a terminal patient have a right to choose something promising? Sure sounds like bureaucratic FDA bullshit to me.

It's pretty hard to ensure it doesn't kill 1/100 people when you're only testing it on 30 people.

The testing process makes sense, try it on a few, try it on a larger sample (30), try it on a really big sample and see how it keeps reacting with all the varying conditions people have, medications they're on and look at the long term results.

Evolution wrote:

If you can reach and inject the tumors with virus one-by-one. Why not inject or cover the tumors with Super-glue? I read about this treatment awhile back. The article claims that Super-glue cut-off the oxygen to the tumors and eventually the tumors died from lack of oxygen.

You should stop getting your news from Weekly World News. It's completely satire. The bat boy story on the side should have been a give away.

if you can engineer a virus to kill cancer, you can make a virus to kill people. this is some kind of 'singularity' for biological warfare. something as contagious as the common cold and as deadly as AIDS.

we ask, "why would anyone work on something like that?", just as people in 1890 must have asked "why would anyone create a super powerful bomb or try to spray their enemies with poisoned gas". what seems barbaric in one age is seen as an opportunity in the next age by despots, tyrants, and others with the war-criminal mindset.

Why can't this sort of thing be a preventative treatment? Basically inject people en masse with something like this and if someone unknowingly is in the first stages of a cancer, it eliminates it before it ever becomes a problem.

Its specific to one of a very large number of ways cancer cells can develop. Treatments like this only work on a fraction of people who have cancer that depends on a specific pathway. Give it to others and there is no benefit. Trying to use it as a preventative measure won't work because any precancerous cells will simply evolve down a different pathway to malignancy.

In fact, the trial was halted early (as noted in the methods section the original protocol called for 44 patients) because of the strength of the results warranted acceleration into a larger patient pool.

Skipping phase 3 trials however doesn't really make sense because a large scale trial is required to determine precisely which patients benefit from the drug and which are at risk of side effects. Without a trial on more then a handful of patients, its difficult to establish who should be treated and when. In particular, its important to note that while 2 patients surviving two years may sound impressive at first glance, this is not a placebo controlled study. Nor is it one that was taken to its original endpoint. Some patients do recovery spontaneously, and the small sample sizes raise the risk of cherry picking. Its important to conduct a more complete, controlled study with a very large population to establish the precise benefit.

if you can engineer a virus to kill cancer, you can make a virus to kill people. this is some kind of 'singularity' for biological warfare. something as contagious as the common cold and as deadly as AIDS.

we ask, "why would anyone work on something like that?", just as people in 1890 must have asked "why would anyone create a super powerful bomb or try to spray their enemies with poisoned gas". what seems barbaric in one age is seen as an opportunity in the next age by despots, tyrants, and others with the war-criminal mindset.

It's not quite that simple, since this research is leveraging defects in the cancerous cells. If such a superbug was that easy to achieve, then Aum Shinrikyo, one of the sources of Anthrax letters, or a despotism would have developed it by now. A straightforward approach would be to make the common cold virus tough enough to survive throughout the body (the receptors it attacks are present on just about every human cell).

We do have the technology to produce an arbitrary DNA sequence, but we're still basically limited to the genes found in nature when it comes to building something useful.

if you can engineer a virus to kill cancer, you can make a virus to kill people. this is some kind of 'singularity' for biological warfare. something as contagious as the common cold and as deadly as AIDS.

This logic is deeply flawed. If you can inject someone, you can kill them. We've had the technology to make injectable poisons since antiquity, if not earlier. What you suggest is nothing new.

Why can't this sort of thing be a preventative treatment? Basically inject people en masse with something like this and if someone unknowingly is in the first stages of a cancer, it eliminates it before it ever becomes a problem.

Its specific to one of a very large number of ways cancer cells can develop. Treatments like this only work on a fraction of people who have cancer that depends on a specific pathway. Give it to others and there is no benefit. Trying to use it as a preventative measure won't work because any precancerous cells will simply evolve down a different pathway to malignancy.

In fact, the trial was halted early (as noted in the methods section the original protocol called for 44 patients) because of the strength of the results warranted acceleration into a larger patient pool.

Skipping phase 3 trials however doesn't really make sense because a large scale trial is required to determine precisely which patients benefit from the drug and which are at risk of side effects. Without a trial on more then a handful of patients, its difficult to establish who should be treated and when. In particular, its important to note that while 2 patients surviving two years may sound impressive at first glance, this is not a placebo controlled study. Nor is it one that was taken to its original endpoint. Some patients do recovery spontaneously, and the small sample sizes raise the risk of cherry picking. Its important to conduct a more complete, controlled study with a very large population to establish the precise benefit.

1. Let anyone who wants to participate in the study. 2. Give the drug to any patient willing to take his chances, under lab conditions, and let that be a complementary study to the phase 3.

if you can engineer a virus to kill cancer, you can make a virus to kill people. this is some kind of 'singularity' for biological warfare. something as contagious as the common cold and as deadly as AIDS.

we ask, "why would anyone work on something like that?", just as people in 1890 must have asked "why would anyone create a super powerful bomb or try to spray their enemies with poisoned gas". what seems barbaric in one age is seen as an opportunity in the next age by despots, tyrants, and others with the war-criminal mindset.

Nature's already done that for us. It's called Smallpox, Ebola, Warburg. No need to engineer anything (although the Soviets created a super-virulent strain of Smallpox by selection).